Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD).

Keywords: biomarkers; chronic kidney disease progression; maladaptive repair; nephrotoxicity; pathophysiology; renal ischemia-reperfusion.

Figure 1

Schematic illustration of the cross-talk between the unfolded protein response (UPR), mitochondria, autophagy, and inflammatory and cell death pathways. In response to cellular stress, unfolded or misfolded proteins accumulate in the endoplasmic reticulum (ER), triggering the UPR, which consists of three ER stress sensors, PERK, ATF6, and IRE1. PERK phosphorylates eIF2α to decrease global protein translation while selectively increasing translation of ATF4, to direct transcription of autophagy genes, a subset of which is controlled by CHOP (26). If the stress is severe or prolonged, then CHOP induction leads to apoptosis. ATF6 is proteolytically cleaved and translocates to the nucleus, where, in combination with spliced Xbp1 (sXbp1), it leads to the transcription of ER chaperones to improve protein folding. IRE1 also promotes mRNA degradation, decreasing overall protein flux to the ER; induces expression of ER-associated degradation components; and is linked to other stress-induced pathways, such as JNK and NFk-B. The UPR counteracts ER stress to restore homeostasis or proceeds to induce cell death pathways via CHOP if the stress is severe or persists. Calcium release from the ER leads to mitochondrial ROS production and amplification of inflammatory and apoptotic pathways. Drp1 on the outer mitochondrial membrane mediates mitochondrial fission, whereas mitofusins (Mfn) are involved in mitochondrial fusion. Persistent ER stress, inflammation, and cell death that override adaptive responses are key factors in maladaptive repair (see Figure 2). For simplicity, some components of the cross-talk between the cellular stress responses have been omitted, and we refer the reader to recent reviews (18, 19). Definitions: ATF6, activating transcription factor 6; BiP, an ER chaperone; CEBP, CCAAT/enhancer binding protein; CHOP, CEBP-homologous protein; eIF2α, eukaryotic initiation factor 2 alpha; IRE1, inositol-requiring kinase 1; JNK, JUN N-terminal kinase; NF-κB, nuclear factor kappa B; PERK, protein kinase RNA-like endoplasmic reticulum kinase; ROS, reactive oxygen species; uXbp1, unspliced Xbp1.

Figure 2

Maladaptive repair following acute kidney injury (AKI) leads to chronic kidney disease (CKD). In response to acute injury, there is activation of cellular stress responses, cell death pathways, and the innate immune response, which in turn lead to endothelial and epithelial dysfunction. If the injury persists or is severe, maladaptive repair mechanisms promote cell and tissue malfunction. Here, inflammation and fibrosis are central to chronic disease. Profibrotic, inflammatory macrophages are recruited. Epithelial cells that arrest in G2/M release cytokines and growth factors to promote ongoing inflammation and fibrosis. Pericytes dissociate from the endothelium to further promote endothelial dysfunction, which leads to microvascular loss. In chronic disease, extracellular matrix– depositing myofibroblasts proliferate and also form from activated, proliferating pericytes. From Reference 12 with permission.